[1,2,4]-Triazole bicyclic adenosine A2a receptor antagonists

ABSTRACT

Compounds having the structural formula I 
     wherein: 
     
         
         
           
             n is 0, 1, 2 or 3; 
             A is C(R 1 ) or N; 
             R 1  and R 1a  are H, (C 1 –C 6 )-alkyl, halo, CN or —CF 3 ; 
             X is —C(O)—, —O—, —SO 0-2 —, or optionally substituted methylene, imino, arylene or heteroaryldiyl; 
             Y is —O—, —SO 0-2 —, or optionally substituted arylene, heteroaryldiyl, or nitrogen-containing heterocycloalkyl, or with certain provisos, a bond; 
             R is optionally substituted-aryl or heteroaryl; and 
             R 2  is optionally substituted-aryl, heteroaryl, arylalkyl or heteroarylalkyl; or R 2 —Y is a fused piperidinyl, substituted piperazinyl or substituted piperidinyl; 
             their use in the treatment of Parkinson&#39;s disease, alone or in combination with other agents for treating Parkinson&#39;s disease, pharmaceutical compositions comprising them and kits comprising the components of the combinations

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 10/304,939, filedNov. 26, 2002, now U.S. Pat. No. 6,875,772, which claims the benefit ofU.S. Provisional Application 60/334,385, filed Nov. 30, 2001.

BACKGROUND

The present invention relates to substituted [1,2,4]-triazole bicyclicadenosine A_(2a) receptor antagonists, the use of said compounds in thetreatment of central nervous system diseases, in particular Parkinson'sdisease, and to pharmaceutical compositions comprising said compounds.

Adenosine is known to be an endogenous modulator of a number ofphysiological functions. At the cardiovascular system level, adenosineis a strong vasodilator and a cardiac depressor. On the central nervoussystem, adenosine induces sedative, anxiolytic and antiepilepticeffects. On the respiratory system, adenosine inducesbronchoconstriction. At the kidney level, it exerts a biphasic action,inducing vasoconstriction at low concentrations and vasodilation at highdoses. Adenosine acts as a lipolysis inhibitor on fat cells and as anantiaggregant on platelets.

Adenosine action is mediated by the interaction with different membranespecific receptors which belong to the family of receptors coupled withG proteins. Biochemical and pharmacological studies, together withadvances in molecular biology, have allowed the identification of atleast four subtypes of adenosine receptors: A₁, A_(2a), A_(2b) and A₃.A₁ and A₃ are high-affinity, inhibiting the activity of the enzymeadenylate cyclase, and A_(2a) and A_(2b) are low-affinity, stimulatingthe activity of the same enzyme. Analogs of adenosine able to interactas antagonists with the A₁, A_(2a), A_(2b) and A₃ receptors have alsobeen identified.

Selective antagonists for the A_(2a) receptor are of pharmacologicalinterest because of their reduced level of side affects. In the centralnervous system, A_(2a) antagonists can have antidepressant propertiesand stimulate cognitive functions. Moreover, data has shown that A_(2a)receptors are present in high density in the basal ganglia, known to beimportant in the control of movement. Hence, A_(2a) antagonists canimprove motor impairment due to neurodegenerative diseases such asParkinson's disease, senile dementia as in Alzheimer's disease, andpsychoses of organic origin.

Some xanthine-related compounds have been found to be A₁ receptorselective antagonists, and xanthine and non-xanthine compounds have beenfound to have high A_(2a) affinity with varying degrees of A_(2a) vs. A₁selectivity. Certain imidazolo- and pyrazolo-su bstitutedtriazolo-pyrimidine adenosine A_(2a) receptor antagonists have beendisclosed previously, for example in WO 95/01356; WO 97/05138; and WO98/52568. Certain pyrazolo-substituted triazolo-pyrimidine adenosineA_(2a) receptor antagonists are disclosed in U.S. Pat. No. 6,630,475.Certain imidazolo-su bstituted triazolo-pyrimid me adenosine A_(2a)receptor antagonists are disclosed in U.S. Pat. No. 6,653,315. U.S. Pat.No. 5,565,460 discloses certain triazolo-triazines as antidepressants;EP 0976753 and WO 99/43678 disclose certain triazolo-pyrimidines asadenosine A_(2a) receptor antagonists; and WO 01/17999 discloses certaintriazolo pyridines as adenosine A_(2a) receptor antagonists.

SUMMARY OF THE INVENTION

The present invention relates to a compound represented by thestructural formula I

or a pharmaceutically acceptable salt thereof, wherein:

A is C(R¹) or N;

R¹ and R^(1a) are independently selected from the group consisting of H,(C₁–C₆)-alkyl, halo, CN and —CF₃;

Y is —O—, —S—, —SO—, —SO₂—, R⁵-heteroaryldiyl, R⁵-arylene or

p and q are independently 2–3;

Q and Q¹ are independently selected from the group consisting of

provided that at least one of Q and Q¹ is

R is R⁵⁻aryl, R⁵⁻heteroaryl, R⁶—(C₂–C₆)alkenyl or R⁶—(C₂–C₆)alkynyl;

R² is R⁵⁻aryl, R⁵⁻heteroaryl, R⁵⁻aryl(C₁–C₆)alkyl or R⁵⁻heteroaryl(C₁–C₆)alkyl;

or R²—Y is

U, V, and W are independently selected from the group consisting of Nand CR¹, provided that at least one of U, V and W is CR¹;

n is 1, 2 or 3; and

-   -   (a) A is C(R¹) and X is —C(R³)(R^(3a))—, —C(O)—, —O—, —S—, —SO—,        —SO₂—, R⁴-arylene, R⁴-heteroaryldiyl, or —N(R⁹)—; or A is C(R¹),        Y is a bond, and X is —C(R³)(R^(3a))—, —C(O)—, —O—, —S—, —SO—,        —SO₂—, R⁴-arylene, —N(R⁹)— or R⁴-heteroaryldiyl, provided that        when X is —N(R⁹)— or R⁴-heteroaryldiyl, R² is not phenyl or        phenyl-(C₁–C₆) alkyl; or    -   (b) A is N, X is —N(R⁹)—, Y is R⁵-arylene and R² is

or n is 2 or 3; and

-   -   (c) A is N and X is —C(R³)(R^(3a))—, —C(O)—, —O—, —S—, —SO—,        —SO₂—, —N(R⁹)—,

-   R⁴-arylene or R⁴-heteroaryldiyl; or A is N, Y is a bond and X is    —C(O)—, —N(R⁹)—,

-   R⁴-arylene or R⁴-heteroaryldiyl; or A is N, Y is —N(R^(9a))—,    —C(O)N(R^(9a))— or —O—(CH₂)₂—N(R^(9a))—, and X is —N(R⁹)—; or A is    N, X is —N(R⁹)—, and Y and R² together are

or n is 0; and

-   -   (d) A is N, Y is a bond, X is —N(R⁹)—, and R² is

-   -    or    -   (e) A is N, X is —N(R⁹)— and Y and R² together are

wherein Z is —C(O)—CH₂—, —C(O)—CH(C₁–C₆ alkyl)-, —CH₂—CH(C₁–C₆ alkyl)-,or —CH(C₁–C₆ alkyl)-CH₂—;

R³ and R^(3a) are independently selected from the group consisting of H,—OH, C₁–C₆ alkyl, hydroxy(C₁–C₆)alkyl, (C₁–C₆)alkoxy(C₁–C₆)alkyl, amino(C₁–C₆)alkyl, (C₁–C₆)alkylamino(C₁–C₆)alkyl and di(C₁–C₆)alkylamino(C₁–C₆)alkyl;

R⁴ is 1–3 substituents selected from the group consisting of H,(C₁–C₆)alkyl, —OH, (C₁–C₆)alkoxy, (C₁–C₆)alkoxy(C₁–C₆)alkoxy, halo,—CF₃, and —CN;

R⁵ is 1–3 substituents independently selected from the group consistingof H, (C₁–C₆)alkyl, —OH, (C₁–C₆)alkoxy, (C₁–C₆)alkoxy(C₁–C₆)alkyl,(C₁–C₆)alkoxy(C₁–C₆)-alkoxy, halo, —CF₃, —CN, —NH₂, (C₁–C₆)alkylamino,di(C₁–C₆)alkylamino, amino(C₁–C₆)-alkyl, (C₁–C₆)alkylamino(C₁–C₆)alkyl,di(C₁–C₆)alkylamino(C₁–C₆)alkyl, (C₁–C₆)alkanoyl-amino,(C₁–C₆)alkanesulfonylamino, (C₁–C₆)alkylthio,(C₁–C₆)alkylthio(C₁–C₆)alkyl, R⁶—(C₂–C₆)alkenyl, R⁶—(C₂–C₆)alkynyl,hydroxy(C₁–C₆)alkyl, (C₁–C₆)alkoxy-C(O)-amino, orheterocycloalkyl(C₁–C₆)alkyl;

R⁶ is 1 to 3 substituents independently selected from the groupconsisting of H, —OH, (C₁–C₆)alkoxy and halo;

R⁷ and R^(7a) are independently selected from the group consisting of H,(C₁–C₆)alkyl, (C₁–C₆)alkoxy(C₁–C₆)alkyl, R⁸-aryl and R⁸-heteroaryl, oran R⁷ and an R^(7a) substituent on the same carbon can form ═O;

R⁸ is 1 to 3 substituents independently selected from H, (C₁–C₆)alkyl,—OH, (C₁–C₆)alkoxy, (C₁–C₆)alkoxy(C₁–C₆)alkoxy, halo, —CF₃, and —CN;

R⁹ and R^(9a) are independently selected from the group consisting of H,(C₁–C₆)alkyl, hydroxy(C₂–C₆)alkyl, (C₁–C₆)alkoxy(C₂–C₆)alkyl,amino(C₂–C₆)alkyl, (C₁–C₆)alkylamino(C₂–C₆)alkyl,di(C₁–C₆)alkylamino(C₂–C₆)alkyl, halo-(C₃–C₆)alkenyl, CF₃—(C₁–C₆)alkyl,(C₃–C₆)alkenyl, (C₃–C₆)cycloalkyl and (C₃–C₆)cycloalkyl-(C₁–C₆)alkyl;and

R¹⁰ is H, —C(O)—O—(C₁–C₆)alkyl, R⁵-aryl, —C(O)—(C₁–C₆)alkyl,—C(O)—(R⁵-aryl) or R⁵-aryl-(C₁–C₆)alkyl.

Another aspect of the invention is a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof formula I in a pharmaceutically acceptable carrier.

Yet another aspect of the invention is a method of treating centralnervous system diseases such as depression, cognitive diseases andneurodegenerative diseases such as Parkinson's disease, senile dementiaor psychoses of organic origin, or stroke, comprising administering atleast one compound of formula I to a mammal in need of such treatment.In particular, the invention is drawn to the method of treatingParkinson's disease comprising administering at least one compound offormula I to a mammal in need of such treatment.

Still another aspect of the invention is a method of treatingParkinson's disease with a combination of at least one compound offormula I and one or more agents useful in the treatment of Parkinson'sdisease, for example dopamine; a dopaminergic agonist; an inhibitor ofmonoamine oxidase, type B (MAO-B); a DOPA decarboxylase inhibitor (DCI);or a catechol-O-methyltransferase (COMT) inhibitor. Also claimed is apharmaceutical composition comprising at least one compound of formula Iand one or more agents known to be useful in the treatment ofParkinson's in a pharmaceutically acceptable carrier. In the methodcomprising the administration of the combination of the invention, oneor more compounds of formula I and one or more other anti-Parkinson'sagents can be administered simultaneously or sequentially in separatedosage forms. Therefore, also claimed is a kit comprising in separatecontainers in a single package pharmaceutical compositions for use incombination to treat Parkinson's disease wherein one container comprisesa pharmaceutical composition comprising an effective amount of acompound of formula I in a pharmaceutically acceptable carrier, andwherein, in separate containers, one or more pharmaceutical compositionseach comprise an effective amount of an agent useful in the treatment ofParkinson's disease in a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

Referring to compounds of formula I above, preferred compounds offormula I are those wherein A is N. R is preferably furyl. R^(1a) ispreferably hydrogen. Another group of preferred compounds is thatwherein X is —O—, —S—, —N(R⁹)— or R⁴-arylene, with compounds wherein Xis —N(R⁹)— being more preferred. R⁹ is preferably C₁–C₆ alkyl, withmethyl and ethyl being most preferred.

Preferred definitions for Y are a bond or piperazinyl (i.e., a group ofthe formula

wherein Q and Q¹ are each nitrogen, p and q are each 2, and each R⁷ andeach R^(7a) is H). R² is preferably R⁵-aryl, more preferably R⁵-phenyl.

When Y and/or R² is

Q is preferably N, Q¹ is preferably N, p and q are each preferably 2,each R⁷ and R^(7a) is preferably hydrogen, and R¹⁰ is preferably—C(O)—O—(C₁–C₆)alkyl, —C(O)—(C₁–C₆)alkyl or —C(O)—(R⁵-aryl).

R⁵ is preferably 1 or 2 substituents selected from the group consistingof H, (C₁–C₆)alkoxy, (C₁–C₆)alkoxy(C₁–C₆)-alkoxy, halo and —CF₃. Morepreferred are H, methoxy, methoxyethoxy, fluoro and chloro.

R⁴ is preferably H, halo or (C₁–C₆)alkyl. R³ and R^(3a) are preferablyindependently selected from H and (C₁–C₆)alkyl. R^(9a) is preferably Hor (C₁–C₆)alkyl. R⁶ is preferably hydrogen.

As used herein, the term alkyl includes saturated straight or branchedcarbon chains.

Halo means fluoro, chloro, bromo or iodo.

Alkenyl means a straight or branched hydrocarbon chain having at leastone double bond. Similarly, alkynyl means a straight or branchedhydrobcarbon chain having at least one triple bond.

Aryl means a single aromatic carbocyclic ring or a bicyclic fusedcarbocyclic ring of 6 to 10 carbon atoms, for example phenyl ornaphthyl.

Heteroaryl means a single ring heteroaromatic group of 5 to 6 atomscomprised of 2 to 5 carbon atoms and 1 to 3 heteroatoms independentlyselected from the group consisting of N, O and S, or a bicyclicheteroaromatic group of 5 to 10 atoms comprised of 1 to 9 carbon atomsand 1 to 3 heteroatoms independently selected from the group consistingof N, O and S, provided that the rings do not include adjacent oxygenand/or sulfur atoms. Examples of single-ring heteroaryl groups arepyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl,pyrimidyl, pyridazinyl and triazolyl. Examples of bicyclic heteroarylgroups are naphthyridyl (e.g., 1,5 or 1,7), imidazopyridyl,pyridopyrimidinyl and 7-azaindolyl. Also included in the definition ofheteroaryl are benzofused heteroaryl groups comprising a heteroaryl ringas defined above fused at adjacent carbon atoms to a phenyl ring.Examples of benzofused heteroaryl groups are indolyl, quinolyl,isoquinolyl, phthalazinyl, benzothienyl (i.e., thionaphthenyl),benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. Allpositional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and4-pyridyl. N-oxides of the ring nitrogens for all heteroaryl groups arealso included. R⁴- and R⁵-substituted heteroaryl refers to such groupswherein substitutable ring carbon atoms have a substituent as definedabove.

Heteroaryldiyl means a heteroaryl ring bonded to two different groups.For example, in the context of this invention, when Y isR⁵-heteroaryldiyl, one ring member is attached to the group —(CH₂)_(n)—,and another ring member is attached to variable R²; the R⁵ substituentsare attached to one or more of the remaining ring carbons. As anexample, a pyridinediyl ring is shown:

Similarly, arylene means a divalent aryl ring, that is, an aryl ringbonded to two different groups, e.g., phenylene.

Heterocycloalkyl means a 3 to 6-membered saturated ring comprised of 2to 5 carbon atoms and 1 or 2 heteroatoms selected from the groupconsisting of N, S and O, provided that two heteroatoms are not adjacentto each other. Typical heterocycloalkyl rings are piperidinyl,piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, tetrahydrothienyl,tetrahydrofuranyl, tetrahydropyranyl and thiomorpholinyl.

When Y and/or R² comprise

each R⁷ and R^(7a) substituent is independently selected from the groupsincluded in the definition above; preferably no more than two of thesubstituents are other than hydrogen.

Certain compounds of the invention may exist in different stereoisomericforms (e.g., enantiomers, diastereoisomers and atropisomers). Theinvention contemplates all such stereoisomers both in pure form and inmixture, including racemic mixtures.

Certain compounds will be acidic in nature, e.g. those compounds whichpossess a phenolic hydroxyl group. These compounds may formpharmaceutically acceptable salts. Examples of such salts may includesodium, potassium, calcium, aluminum, gold and silver salts.

Certain basic compounds also form pharmaceutically acceptable salts,e.g., acid addition salts. For example, pyrido-nitrogen atoms may formsalts with strong acid, while compounds having basic functionality suchas amino groups also form salts with weaker acids. Examples of suitableacids for salt formation are hydrochloric, sulfuric, phosphoric, acetic,citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic,maleic, methanesulfonic and other mineral and carboxylic acids wellknown to those skilled in the art. The salts are prepared by contactingthe free base form with a sufficient amount of the desired acid toproduce a salt in the conventional manner. The free base forms may beregenerated by treating the salt with a suitable dilute aqueous basesolution such as dilute aqueous NaOH, potassium carbonate, ammonia andsodium bicarbonate. The free base forms differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the acid and base salts are otherwise equivalentto their respective free base forms for purposes of the invention.

All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of formula I are prepared by general methods known in the art.Preferably, the compounds of formula I are prepared by the methods shownin the following reaction schemes. In the Schemes and examples thatfollow, the following abbreviations are used: Ph is phenyl, Me ismethyl, Et is ethyl, TFA is trifluoroacetic acid, BSA isN,O-bis(trimethylsilyl)acetamide, DMF is dimethylformamide, EtOAc isethyl acetate, THF is tetrahydrofuran, and DBU is1,8-diazabicyclo[5.4.0]undec-7-ene.

Compounds of formula IIa where A is C(R¹) can be prepared by methodsdescribed in application WO 01/11799. In addition, compounds wherein Yis not a bond can be prepared by methods illustrated in Scheme 1.

Where X is arylene, an intermediate of type 2 may be activated, e.g. toa chloride, which may then be reacted with a nucleophile 4 (e.g.,Y=piperazinyl) to provide IIa. Alternatively, bromide 3 may be reactedwith a nucleophile of type 5 provide IIa.

Compounds of formula IIb where A is N, and X is —O—, —S—, or —N(R⁹)— canbe prepared by methods described in Schemes 2 and 3.

Chloride 6 is treated with an amine, alcohol or thiol in the presence ofbase to yield 7. Reaction with the appropriate hydrazide yields 8.Dehydrative cyclization with an agent such as BSA then yields thedesired compound of formula IIb.

In a variant of this scheme, R in the hydrazide RCONHNH₂ may be aremovable protective group such a t-butoxy or benzyloxy. In such a case,deprotection of 8 leads to 8a,

which may be acylated with RCOOH or the corresponding acid chloride,anhydride, or mixed anhydride. This produces a new 8, which may beconverted to the desired compound of formula IIb.

In Scheme 3, the order of the steps is reversed in order to preparecompounds of formula IIb.

In Scheme 4, compounds of formula IIc, wherein A is N and X is—C(R³)(R^(3a))— are prepared.

Keto-ester 11 is converted to pyrimidine 12, then to chloride 13.Reaction with a hydrazide provides 14, and BSA cyclization yields 15.The olefinic bond is cleaved to give aldehyde 16. When Y in IIc islinked to the alkylene chain through a nitrogen atom, reductiveamination of 16 yields the desired compounds IIc.

A method of preparing compounds of formula IId or IIe where A is N and Xis —S—, —SO— or —SO₂— is described in Scheme 5.

Chloride 6 is reacted with Na₂S and the intermediate then alkylated witha chloride or equivalent to give 7a. This is then converted to lid as inScheme 2. Subsequent oxidation is employed to prepare the sulfoxide orsulfone of formula IIe.

For compounds IIf where R² contains an R¹⁰ moiety, such moieties may bemodified, as shown in Scheme 6. When R¹⁰ is t-butoxycarbonyl orbenzyloxycarbonyl or the like, the group may be converted to H, e.g. bytreatment respectively with acid such as TFA or by hydrogenolysis. Theresulting 17 may then be converted to a different compound IIf. ForR¹⁰=alkoxycarbonyl or aroyl, acylation may be achieved with an alkylchloroformate or aroyl chloride or similar acylating agent. ForR¹⁰=aralkyl, reductive alkylation of 17 may be achieved with an arylaldehyde and NaBH(OAc)₃.

Similar methodology can be employed to prepare compounds of formula IIg:

PREPARATION 1

Step 1:

To 2-(4-fluorophenyl)ethanol (2.80 g, 20.0 mmol) add SOCl₂ (7.14 g, 60mmol). Add two drops DMF and heat at 70° C. for 3 h. Concentrate,partition between hexane and ice-water, dry (MgSO₄), and concentrate toobtain the chloride as an almost colorless oil.

Step 2:

Combine the chloride of Step 1 (1.00 g, 6.3 mmol) with 40% aqueousCH₃NH₂ (20 g, 260 mmol). Heat in a sealed tube at 65° C. for 2.5 h.Allow to cool, dilute with water, and extract with EtOAc. Extract theEtOAc with 0.5M HCl, basify with 20% NaOH, and extract with CH₂Cl₂. Dry(MgSO₄) and concentrate to obtain the title amine as a yellow oil.

Similarly, convert the corresponding alcohols to the following amines:

Similarly, convert the corresponding alcohols via the mesylates into thefollowing amines:

PREPARATION 2

Combine 1-(2,4-difluorophenyl)piperazine (0.50 g, 2.5 mmol),2-bromoethanol (0.37 g, 3.0 mmol), and Et₃N (0.30 g, 3.0 mmol) in THF (5ml). Heat at reflux 4 h, allow to cool, and partition between water andCH₂Cl₂. Wash the CH₂Cl₂ with brine, dry (MgSO₄), and concentrate toobtain the title alcohol as a yellow oil.

Similarly prepare:

Prep. 2-2

Prep. 2-3

Prep. 2-4

Prep. 2-5

Prep. 2-6

Prep. 2-7

Prep. 2-8

Prep. 2-9

PREPARATION 3

Step 1:

To the product of Preparation 2 (0.50 g, 2.1 mmol) in CH₂Cl₂ (10 ml) addSOCl₂ (0.49 g, 4.2 mmol). Add two drops DMF and stir 4 h. Concentrate,partition between EtOAc and water, dry (MgSO₄), and concentrate toobtain the chloride as an almost colorless oil.

Step 2:

Combine the product of Step 1 (0.51 g, 2.0 mmol) with 40% aqueous CH₃NH₂(10 ml, 130 mmol) in EtOH (10 ml). Heat in a sealed tube at 80° C. for 2h, allow to cool, concentrate, and partition between EtOAc and water.Dry (MgSO₄) and concentrate to obtain the title amine as a yellow oil.

Similarly prepare:

Prep. 3-2 

Prep. 3-3 

Prep. 3-4 

Prep. 3-5 

Prep. 3-6 

Prep. 3-7 

Prep. 3-8 

Prep. 3-9 

Prep. 3-10

Prep. 3-11

Prep. 3-12

Prep. 3-13

Prep. 3-14

Prep. 3-15

Prep. 3-16

Prep. 3-17

Prep. 3-18

Prep. 3-19

Prep. 3-20

Prep. 3-21

Prep. 3-22

Prep. 3-23

Prep. 3-24

Prep. 3-25

Prep. 3-26

Prep. 3-27

Prep. 3-28

Prep. 3-29

Prep. 3-30

Prep. 3-31

Prep. 3-32

Prep. 3-33

Prep. 3-34

PREPARATION 4

Combine 2,4-difluorobromobenzene (4.0 g, 20.7 mmol), 2-methylpiperazine(24.9 g, 249 mmol), NaO-tBu (2.79 g, 29.0 mmol), ±-BINAP (0.77 g, 1.2mmol), and Pd₂(dba)₃ (0.24 g, 0.41 mmol) in toluene (40 ml). Heat atreflux 16 h, allow to cool, and extract with 1N HCl (4×50 ml). Basifywith NaOH to pH 13 and extract with CH₂Cl₂. Dry (MgSO₄) and concentrateto give the product as a brown oil.

PREPARATION 5

Step 1:

Combine 2,4-difluoroaniline (10.0 g, 77.4 mmol) and2-bromoethylamine•HBr (15.9 g, 77.4 mmol) in toluene (100 ml). Heat atreflux 16 h, allow to cool, and remove the toluene layer. Dissolve theoily layer in water, basify with NaOH to pH 11, and extract with CH₂Cl₂.Dry (MgSO₄), concentrate, and distill at 120–30° C. (1 mm).Chromatograph on silica to obtain the product as a brown oil.

Step 2:

Dissolve the product of Step 1 (3.0 g, 17 mmol) in CH₂Cl₂ (25 ml). Coolin ice and add Et₃N (5.3 ml, 38 mmol), followed by 2-bromopropionylbromide (2.1 ml, 19 mmol). Allow to warm to RT, stir 16 h, cool in ice,and add more bromide (1.1 g) and Et₃N (1.0 g). Allow to warm to RT, stir2 h, wash with water, dry (MgSO₄) and concentrate to obtain crude brownoil.

Step 3:

Treat the product of Step 2 (5.86 g, 19 mmol) with DIPEA (2.97 g, 23mmol) and KI (1.58 g, 9.5 mmol) in DMF (15 ml). Heat at 80° C. 18 h,allow to cool, concentrate and chromatograph on silica to obtain theproduct as a brown solid.

Step 4:

Dissolve the product of Step 3 (1.33 g, 5.86 mmol) in THF (20 ml) andcool in ice. Add slowly 1.0M BH₃. THF solution (15 ml, 15 mmol). Allowto warm to RT, stir 1 h, add additional BH₃. THF solution (7 ml), andstir 2 h. Cool in ice and quench slowly with MeOH. Concentrate andpartition with CH₂Cl₂ and 0.5N NaOH. Dry (MgSO₄), concentrate and purifyby PLC to obtain the title compound as a yellow oil.

PREPARATION 6

Step 1:

Combine N-benzyl-4-piperidone (3.57 ml, 20 mmol), 3-ethoxymethacrolein(3.76 ml, 30 mmol), NH₄OAc (0.82 g, 11 mmol), and 28% aqueous ammonia(4.17 ml, 62 mmol). Heat in a sealed tube at 90° C. 48 h, allow to cool,and partition between Et₂O and 1N NaHCO₃. Extract the Et₂O with 1N HCland basify the extract with NaOH to pH 13. Extract with Et₂O, dry(MgSO₄) and concentrate. Subject the oil to Kugelrohr distillation at0.5 mm, collecting 90–160° C. to obtain the product as an orange oil.

Step 2:

Dissolve the product of Step 1 (1.73 g, 7.3 mmol) in 10:1 MeOH/conc. HCl(44 ml). Add 10% Pd/C (0.40 g) and hydrogenate at 60 psi for 18 h.Filter through Celite and concentrate to solid. Dissolve in 95% EtOH andadd NaO-tBu (0.70 g). Concentrate, treat with EtOH, filter, andconcentrate to leave the crude product as a yellow solid.

Step 3:

Combine the product of Step 2 (0.200 g, 1.35 mmol),1-bromo-2-chloroethane (0.45 ml, 5.4 mmol), and DIPEA (0.28 ml, 1.6mmol) in DMF (10 ml). Stir 48 h, add 1N NaOH (5 ml), and extract withEt₂O. Dry (MgSO₄), concentrate and purify by PLC to obtain the productas a yellow oil.

Step 4:

Combine the product of Step 3 (0.22 g, 1.0 mmol), with 40% aqueous MeNH₂(5.0 ml) and EtOH (5 ml). Heat in a sealed tube at 100° C. 3 h, allow tocool, add 1N NaOH (3 ml), concentrate and partition between CH₂Cl₂ andwater. Dry (MgSO₄), and concentrate to obtain the title compound as alight brown oil.

PREPARATION 7

Combine 4-fluorobenzyl chloride (1.74 g, 12.0 mmol),N,N′-dimethylethylene-diamine (3.17 g, 36 mmol), KI (0.20 g, 1.2 mmol),and NaHCO₃ (1.51 g, 18 mmol) in EtOH (20 ml). Heat at reflux 4 h,filter, and concentrate. Partition with 1N HCl and EtOAc and basify theaqueous layer with NaOH. Extract with CH₂Cl₂, dry (MgSO₄), andconcentrate. Distill at 0.5 mm up to 100° C. to obtain the titlecompound as a colorless liquid.

PREPARATION 8

Combine 2,4-difluorfluoro-N-methylaniline (1.00 g, 6.98 mmol) and 4MHCl/dioxane (10 ml) in MeOH (10 ml). Concentrate to a white solid. Add3-methyl-2-oxazolidinone (0.60 g, 6.98 mmol). Heat at 160° C. 18 h.Allow to cool, basify with NaOH, and extract with CH₂Cl₂. Dry (MgSO₄),concentrate, and chromatograph on silica to obtain the title compound asa yellow oil. This contains some of the product with aniline methylremoved.

EXAMPLE 1

Step 1:

Combine 2-amino-4,6-dichloropyrimidine (0.50 g, 3.0 mmol),2-(4-methoxy-phenyl)ethylamine (0.51 g, 3.4 mmol) and K₂CO₃ (0.46 g, 3.4mmole) in EtOH (8 ml). Heat in a sealed tube at 90° C. 1 h. Stir another16 h, dilute with water (15 ml), filter, and purify on PLC to obtain thechloropyrimidine as a white solid.

Step 2:

Combine the product of Step 1 (0.30 g, 1.08 mmol), 2-furoic hydrazide(0.16 g, 1.3 mmol), and 1.0N HCl (0.4 ml) in EtOH (3 ml). Heat in asealed tube at 90° C. for 16 h. Basify with NH₃, extract with EtOAc, andpurify on PLC to obtain the hydrazide as a yellow solid.

Step 3:

Add the product of Step 2 to BSA (4.0 ml). Heat at 120° C. 18 h. Pourinto CH₃OH, concentrate, and purify on PLC to obtain the title compoundas a white solid, MS: m/e 351 (M+1).

In a similar manner, prepare the following compounds (Et₃N employed asbase in Step 1):

wherein R²—Y—(CH₂)_(n)—N(R⁹)— is as defined in the table:

Ex- am- ple R²—Y—(CH₂)_(n)—N(R⁹)— MS m/e 1-2 

365 1-3 

455 1-4 

411 1-5 

353 1-6 

367 1-7 

369 1-8 

397 1-9 

379 1-10

467,469 1-11

463 1-12

441 1-13

479 1-14

561

Similarly, by employing benzoic hydrazide in place of furoic hydrazide,prepare Example 1-15 as a yellow solid.

1-15: MS: m/e 503 (M+1)

EXAMPLE 2

Step 1:

To NaH (60% in oil, 0.16 g, 4.0 mmol) in THF (6 ml) add2-(4-methoxy-phenyl)ethanol (0.46 g, 3.0 mmol). Stir 0.5 h and add2-amino-4,6-dichloropyrimidine (0.50 g, 3.0 mmol). Heat at reflux 24 h.Filter, wash with CH₂Cl₂, concentrate, and purify on PLC to obtain thechloropyrimidine as a white solid.

Conduct Steps 2 and 3 as in Example 1 to obtain the title compound as awhite solid, MS: m/e 352 (M+1).

In a similar manner prepare the following:

wherein R²—Y—(CH₂)_(n)—O— is as defined in the table:

Example R²—Y—(CH₂)_(n)—O— MS m/e 2-2

366 2-3

442 2-4

398 2-5

480 2-6

548

Similarly, by employing 5-chloro-2-furoic hydrazide in place of furoichydrazide, prepare Example 2-7 as a yellow solid:

2-7: MS m/e 514, 516 (M+1)

EXAMPLE 3

Step 1:

Combine 3-iodobenzyl alcohol (2.00 g, 8.5 mmol), acrylonitrile (0.67 ml,10.2 mmol), and Et₃N (4.3 ml, 26 mmol) in DMF (30 ml). Purge with N₂ andadd (Ph₃P)₂PdCl₂ (0.12 g, 0.17 mmol). Heat in a sealed vessel 3 days at120°, allow to cool, and partition between CH₂Cl₂ and sat. NaHCO₃. Dry(MgSO₄) and concentrate. Chromatograph on silica to obtain the nitrileas a yellow oil.

Step 2:

Combine the product of Step 1 (1.25 g, 7.9 mmol), t-butyldimethylsilylchloride (1.42 g, 9.4 mmol), and imidazole (0.69 g, 10.2 mmol) in DMF(15 ml). Stir 7 h, partition between Et₂O and water, dry the Et₂O(MgSO₄) and concentrate to obtain the silyl ether as a colorless oil.

Step 3:

To a boiling suspension of potassium t-butoxide (2.34 g, 24.4 mmol) inTHF (20 ml) add dropwise over 5 h a solution of the product of Step 2(2.15 g, 7.9 mmol) and 3-(2-furyl)-5-phenylsulfonylmethyl[1,2,4]triazole(2.27 g, 7.9 mmol) in THF (20 ml). Heat 18 h, allow to cool, add water(30 ml), and extract 3× with 5% CH₃OH/CH₂Cl₂. Dry (MgSO₄), concentrate,and chromatograph on silica to obtain the bicyclic as a yellow solid.

Step 4:

To the product of Step 3 (0.75 g, 1.8 mmol) in THF (5 ml) addtetrabutyl-ammonium fluoride (1.0M in THF, 2.14 ml). Stir 2 h,concentrate, and purify on PLC to obtain the alcohol as a yellow solid.

Step 5:

To the product of Step 4 (0.200 g, 0.65 mmol) in CH₂Cl₂ (10 ml) addSOCl₂ (0.19 ml, 2.6 mmol) and two drops pyridine. Heat at reflux 1 h,allow to cool, wash with 1N NaOH, concentrate, dry (MgSO₄), andconcentrate to obtain the crude chloride as a yellow solid.

Step 6:

Combine the product of Step 5 (0.090 g, 0.28 mmol) with1-(2,4-difluoro-phenyl)piperazine (0.065 g, 0.33 mmol) anddiisopropylethylamine (0.058 ml) in DMF (4 ml). Stir 3 days, heat to 60°for 3 h, allow to cool, concentrate, and purify on PLC to obtain thetitle compound as a white solid: MS m/e=487 (M+1).

In similar fashion, employ 1-(4-(2-methoxyethoxy)phenyl)piperazine toobtain Example 3-2 as a white solid.

3-2: MS m/e 525

EXAMPLE 4

Step 1:

Combine 2-amino-4,6-dichloropyrimidine (0.50 g, 3.0 mmol) and Na₂S (0.29g, 3.7 mmole) in DMF (6 ml). Stir for 1 h. Add 4-methoxyphenethylchloride (0.64 g, 3.77 mmol) and heat at 80° C. 18 h. Add water andextract with EtOAc. Purify on PLC to obtain the chloropyrimidine as awhite solid.

Steps 2 and 3:

Conduct as for Example 1, Steps 2 and 3, to obtain the title compound asa white solid, MS: m/e 368 (M+1).

In a similar manner, from the products of Preparation 3-2, Step 1, andPreparation 3-6, Step 1, prepare the following:

4-2: MS: m/e 496

4-3: MS: m/e 564

4-4: MS m/e 458

EXAMPLE 5

Step 1:

Combine 2-amino-4,6-dichloropyrimidine (1.00 g, 6.10 mmol), 2-furoichydrazide (0.97 g, 7.7 mmol) and K₂CO₃ (1.13 g, 8.2 mmole) in EtOH (6ml). Heat in a sealed tube at 100° C. 18 h. Allow to cool, filter, washwith water to obtain product. Extract the filtrate with EtOAc,concentrate and recrystallize from EtOAc to obtain additional product asa yellow solid.

Step 2:

Add the product of Step 1 (0.50 g, 2.13 mmol) to BSA (15 ml). Heat at120° C. 18 h, allow to cool, and pour into CH₃OH (20 ml). Concentrateand heat at reflux in 50% EtOH (40 ml) 1 h. Remove EtOH and extract withCH₂Cl₂. Dry and concentrate to obtain the product as a white solid.

Step 3:

Combine the product of Step 2 (0.093 g, 0.39 mmol), the product ofPreparation 3-2 (0.127 g, 0.43 mmol), and DBU (0.059 ml, 0.42 mmol) inDMF (2 ml). Heat at 140° C. 2 h, concentrate and purify on PLC to obtainthe title compound as a yellow solid, MS: m/e 493 (M+1).

In a similar manner, employing the appropriate amine from Preparation 1or Preparation 3, prepare the following:

Example R²—Y—(CH₂)_(n)—N(R⁹)— MS m/e 5-2 

339 5-3 

499 5-4 

495 5-5 

469 5-6 

507 5-7 

537 5-8 

533 5-9 

449 5-10

481 5-11

519 5-12

481 5-13

483 5-14

485 5-15

519 5-16

523 5-17

521 5-18

561 5-19

553,555 5-20

523 5-21

515,517 5-22

499 5-23

511 5-24

497 5-25

537 5-26

521 5-27

473 5-28

469 5-29

469 5-30

463 5-31

405 5-32

396 5-33

401,403 5-34

400 5-35

386 5-36

415,417 5-37

447,449 5-38

399,401 5-39

411 5-40

417 5-41

414 5-42

414 5-43

400

In a similar fashion, employ 2-amino-4,5,6-trichloropyrimidine asstarting material to obtain Example 5-44 as a yellow solid.

5-44: MS m/e 489, 491 (M+1)

EXAMPLE 6

Step 1:

Combine 2-amino-4,6-dichloropyrimidine (0.477 g, 2.73 mmol), the productof Preparation 3-2 (0.800 g, 2.73 mmol) and DIPEA (0.57 ml, 3.27 mmole)in DMF (5 ml). Heat in a sealed tube at 90° C. 14 h. Allow to cool,concentrate, and chromatograph on silica to obtain the product as ayellow solid.

Step 2:

Combine the product of Step 1 (1.07 g, 2.54 mmol), t-butyl carbazate(1.01 g, 7.61 mmol) and 4.0M HCl/dioxane (0.76 ml, 3.04 mmole) in EtOH(12 ml). Heat in a sealed tube at 100° C. 18 h, allow to cool, and add2N NH₃/MeOH M (10 ml). Concentrate and chromatograph on silica to obtainthe product as a yellow solid.

Step 3:

Dissolve the product of Step 2 (0.90 g, 1.74 mmol) in CH₂Cl₂—MeOH (1:17,20 ml). Add 4.0M HCl/dioxane (5.0 ml, 20 mmole). Stir 18 h, concentrate,add 1N NaOH (10 ml), and extract with CH₂Cl₂. Dry (MgSO₄), concentrate,and chromatograph on silica to obtain the product as a yellow solid.

Step 4:

To a solution of 3-cyanobenzoic acid (0.047 g, 0.32 mmol) in DMF (3 ml)add the product of Step 3 (0.110 g, 0.26 mmol), EDCI (0.061 g, 0.32mmol), HOBt.H₂O (0.043 g, 0.32 mmol), and NMM (0.035 ml, 0.32 mmol).Stir 3 h, concentrate, and purify by PLC to obtain the product as ayellow solid.

Step 5:

Add the product of Step 4 (0.101 g, 0.18 mmol) to BSA (6.0 ml). Heat at120° C. 18 h, allow to cool, concentrate, add MeOH (20 ml), stir 0.5 h,concentrate, and purify by PLC to obtain the title compound as a yellowsolid, MS: m/e 528 (M+1).

In a similar fashion, employ the product of Preparation 3 as startingmaterial to obtain Example 6-2 as a white solid.

EX. 6-2: MS: m/e 490 (M+1)

EXAMPLE 7

Step 1:

Combine 2-amino-4,6-dichloropyrimidine (0.515 g, 3.14 mmol) and Na₂S(0.294 g, 3.76 mmole) in DMF (3 ml). Stir for 1 h. Add the product ofPreparation 3, Step 1 (0.900 g, 3.45 mmol) in DMF (2 ml) and heat at 80°C. 18 h. Allow to cool, add CH₂Cl₂, and filter. Concentrate andchromatograph on silica to obtain the product as a yellow solid.

Steps 2–5:

Treat the product of Step 1 according to Example 6, Steps 2–5, to obtainthe title compound as an off-white solid, MS: m/e 493 (M+1).

EXAMPLE 8

Step 1:

Combine ethyl 3-oxo-6-heptenoate (6.68 g, 39.2 mmol) and guanidinecarbonate (12.7 g, 70.6 mmol) in EtOH (100 ml). Heat at reflux 20 h,allow to cool, and add CH₂Cl₂ (100 ml). Filter, concentrate, andchromatograph on silica to obtain a white solid.

Step 2:

Treat the product of Step 1 (2.35 g, 14.2 mmol) with POCl₃ (20 ml). Heatat reflux 2 h, concentrate, pour onto ice water, and basify with NaOH topH9. Extract with CH₂Cl₂, dry (MgSO₄), concentrate, and chromatograph onsilica to obtain a yellow oil.

Step 3:

Combine the product of Step 2 (0.90 g, 4.9 mmol), 2-furoic hydrazide(0.865 g, 6.86 mmol) and 4.0M HCl/dioxane (1.47 ml, 5.88 mmol) in EtOH(10 ml). Heat in a sealed tube at 100° C. 18 h, allow to cool, and add2N NH₃/MeOH (10 ml). Concentrate and chromatograph on silica to obtainthe product as a yellow solid.

Step 4:

Add the product of Step 3 (0.8 g, 2.9 mmol) to BSA (10 ml). Heat at 130°C. 6 h, allow to cool, and concentrate. Wash with water to obtain ayellow solid.

Step 5:

Dissolve the product of Step 4 (0.10 g, 0.39 mmol) in THF (8 ml), coolin ice, add water (5 ml), then NaIO₄ (0.419 g, 1.96 mmol). Add twocrystals OsO₄ and stir 5 h. Partition with CH₂Cl₂ and water, dry(MgSO₄), concentrate, and purify by PLC to obtain a yellow solid.

Step 6:

Dissolve the product of Step 5 (0.080 g, 0.31 mmol) in CH₂Cl₂ (5 ml).Add 1-(2,4-difluorophenyl)piperazine (0.185 g, 0.93 mmol), AcOH (0.30ml), and NaCNBH₃ (0.066 g, 0.31 mmol). Stir 18 h, concentrate, andpurify by PLC to obtain the title compound as a white solid, MS: m/e=440(M+1).

In a similar fashion, employ the appropriate aryl-piperazine to obtainExample 8-2 as a yellow powder.

EX. 8-2: MS: m/e=478 (M+1)

EXAMPLE 9

Step 1:

Dissolve 1-(2-hydroxyethy)piperazine (3.25 g, 25 mmol) in THF (40 ml)and cool in ice. Add, portionwise, Boc₂O (5.45 g, 25 mmol). Allow towarm, stir 3 h, concentrate, and treat with hot hexane (50 ml). Cool to−15° C. and decant the hexane to leave a viscous orange oil.

Step 2:

Combine the product of Step 1 (3.49 g, 15.0 mmol) and Et₃N (1.72 g, 17.0mmol) in CH₂Cl₂ (40 ml) and cool in ice. Add, dropwise, MsCl (1.96 g,17.0 mmol) in CH₂Cl₂ (10 ml). Allow to warm, stir 0.5 h, andconcentrate. Partition between Et₂O and water, dry (MgSO₄) andconcentrate to give the crude product as viscous oil with solid.

Step 3:

Combine the crude product of Step 2 (4.6 g, ˜15 mmol) with 40% aqueousMeNH₂ (35 g, 0.45 mol) and EtOH (35 ml). After 1 h, concentrate andpartition between CH₂Cl₂ and 1N NaOH. Dry (MgSO₄) and concentrate toobtain the crude product as a yellow oil.

Step 4:

Combine the crude product of Step 3 (0.46 g, ˜1.5 mmol) with the productof Example 5, Step 2 (0.236 g, 1.00 mmol), and K₂CO₃ (0.207 g, 1.50mmol) in DMF (8 ml). Heat in a sealed tube at 130° C. 18 h, concentrateand partition between EtOAC (10% MeOH) and water. Dry (MgSO₄),concentrate and chromatograph on silica and triturate with Et₂O toobtain the title compound as yellow solid, MS: m/e=443 (M+1).

EXAMPLE 10

Step 1:

Combine 2-(4-bromophenyl)ethanol (4.88 g, 24.3 mmol), piperazine (12.5g, 146 mmol), NaO-tBu (3.27 g, 34.0 mmol), ±-BINAP (0.91 g, 1.5 mmol),and Pd₂(dba)₃ (0.28 g, 0.49 mmol) in toluene (40 ml). Heat at reflux 2h, allow to cool, and extract with 1N HCl (4×50 ml). Basify with NaOH topH 13 and extract with CH₂Cl₂. Dry (MgSO₄) and concentrate to give abrown oil.

Step 2:

Dissolve the product of Step 1 (4.02 g, 19.5 mmol) in CH₂Cl₂ (50 ml).Add Boc₂O (4.51 g, 20.5 mmol) and then Et₃N (3.26 ml, 23.4 mmol). Stir 1h and wash with 1N NaOH. Dry (MgSO₄), concentrate and chromatograph onsilica to obtain a brown oil.

Step 3:

Combine the product of Step 2 (1.00 g, 3.26 mmol) and Et₃N (0.73 ml, 5.2mmol) in CH₂Cl₂ (20 ml). Cool in ice and add gradually MsCl (0.30 ml,3.9 mmol). Stir 1 h, wash with sat. NaHCO₃, dry (MgSO₄) and concentrateto obtain a yellow oil.

Step 4:

Dissolve the product of Step 3 (1.15 g, 2.99 mmol) in EtOH (10 ml). Add40% aqueous MeNH₂ (10 ml) and heat in a sealed tube at 100° C. 16 h,allow to cool, concentrate, and partition between CH₂Cl₂ and 1N NaOH.Dry (MgSO₄), concentrate, and purify by PLC to obtain a yellow oil.

Step 5:

Combine the product of Step 4 (0.466 g, 1.46 mmol), the product ofExample 5, Step 2 (0.229 g, 0.97 mmol), and K₂CO₃ (0.202 g, 1.46 mmol)in DMF (8 ml). Heat in a sealed tube at 140° C. 18 h, concentrate andpurify on PLC to obtain the title compound as a yellow foam,concentrate, and purify by PLC to obtain the product as a yellow oil MS:m/e=519 (M+1).

EXAMPLE 11

Dissolve the compound of Example 10 (0.215 g, 0.41 mmol) in 1:1CH₂Cl₂—MeOH (10 ml) and add 4M HCl/dioxane (2.0 ml). Stir 18 h and add7M NH₃/MeOH (4.0 ml). Concentrate, and chromatograph on silica to obtainthe product as a white foam, MS: m/e=419 (M+1).

EXAMPLE 12

Dissolve the compound of Example 11 (0.050 g, 0.12 mmol) in CH₂Cl₂ (5ml). Add DIPEA (0.031 ml, 0.18 mmol) and AcCl (0.010 ml, 0.14 mmol).Stir 1 h, concentrate, and purify by PLC to obtain the title compound asa white foam, MS: m/e=461 (M+1).

EXAMPLE 13

Step 1:

Dissolve 1-(2,4-difluorophenyl)piperazine (1.00 g, 5.05 mmol) in CH₂Cl₂(5 ml). Cool in ice and add N-methylmorpholine (0.66 ml, 6.05 mmol)together with chloroacetyl chloride (0.45 ml, 5.6 mmol). Stir 2 h,concentrate, and partition between EtOAc and water. Dry (MgSO₄) andconcentrate to obtain a yellow oil.

Step 2:

Dissolve the product of Step 1 (1.49 g, 5.4 mmol) in EtOH (10 ml). Add40% aqueous MeNH₂ (15 ml) and heat in a sealed tube at 100° C. 48 h,allow to cool, concentrate, and partition between CH₂Cl₂ and 1N NaOH.Dry (MgSO₄) and concentrate to obtain a yellow oil.

Step 3:

Combine the product of Step 2 (0.137 g, 0.51 mmol), the product ofExample 5, Step 2 (0.080 g, 0.34 mmol), and K₂CO₃ (0.070 g, 0.51 mmol)in DMF (4 ml). Heat in a sealed tube at 140° C. 18 h, concentrate andpurify on PLC to obtain the title compound as a yellow foam,concentrate, and purify by PLC to obtain the product as a yellow solidMS: m/e=469 (M+1).

In similar fashion, using 2-bromopropionyl bromide in Step 1, prepareExample 13-2 as an off-white powder.

Ex. 13-2: MS: m/e=483 (M+1)

EXAMPLE 14

Step 1:

Dissolve the product of Example 13-2, Step 2 (0.405 g, 1.43 mmol) in THF(10 ml). Add 1.0M LiAlH₄/Et₂O (0.86 ml, 0.86 mmol). Heat at 60° C. 4 h,allow to cool, add water (0.065 ml), then 15% NaOH (0.065 ml), thenwater (3×0.065 ml). Filter and concentrate. Partition between CH₂Cl₂ and1N HCl. Basify the aqueous to pH 12 with NaOH, extract with CH₂Cl₂, dry(MgSO₄) and concentrate. Purify by PLC to obtain a colorless oil.

Step 2:

Treat the product of Step 1 with the product of Example 5, Step 2,following the procedure of Example 13, Step 3, to obtain the titlecompound as a yellow oil, MS: m/e=469 (M+1).

EXAMPLE 15

Step 1:

Combine 1-(2,4-difluorophenyl)piperazine (1.98 g, 10.0 mmol), ethyl2-bromo-propionate (1.81 g, 10.0 mmol), and K₂CO₃ (1.38 g, 10.0 mmol) inEtOH (15 ml). Heat at 80° C. 18 h, add more bromide (0.07 g), heatanother 5 h, allow to cool, filter, and concentrate. Partition betweenEt₂O and water. Dry (MgSO₄) and concentrate to obtain a colorlessliquid.

Step 2:

Combine the product of Step 1 (2.38 g, 8.0 mmol) with 40% aqueous MeNH₂(9.3 g, 0.12 mol) and EtOH (5 ml). Heat in a sealed tube at 80° C. 18 h,allow to cool, concentrate, and partition between EtOAc and water. Dry(MgSO₄) and concentrate to obtain a yellow solid. Recrystallization fromMeOH-water gives white needles, m.p. 112–3° C.

Step 3:

Treat the product of Step 2 with LiAlH₄ as in Example 14, Step 1 (24 hheating) to obtain a yellow oil.

Step 4:

Treat the product of Step 3 with the product of Example 5, Step 2,following the procedure of Example 13, Step 3), to obtain the titlecompound as a colorless oil, MS: m/e=451 (M+1).

EXAMPLE 16

Dissolve the compound of Example 5-41 (0.206 g, 0.50 mmol) in 1:1MeOH—CH₂Cl₂ (10 ml). Add 4.0M HCl/dioxane (4.0 ml). Stir 2 h and quenchwith 2M NH₃/MeOH. Concentrate and chromatograph on silica to obtain thetitle compound as a yellow oil, MS: m/e 314 (M+1).

In a similar manner prepare Examples 16-2 and 16-3.

Ex. 16-2: MS: m/e 314 (M+1)

Ex. 16-3: MS: m/e 300 (M+1)

EXAMPLE 17

Combine the compound of Example 16 (0.070 g, 0.22 mmol),4-methoxybenzoyl chloride (0.058 g, 0.34 mmol), and DIPEA (0.058 g, 0.45mmol) in DMF (4 ml). Stir 2 h, concentrate, and purify by PLC to obtainthe title compound as a yellow solid, MS: m/e 448 (M+1).

In similar fashion, convert the respective compounds of Example 16 toExamples 17-2 and 17-3.

Ex. 17-2: MS: m/e 448 (M+1)

Ex. 17-3: MS: m/e 434 (M+1)

EXAMPLE 18

Combine the compound of Example 17-2 (0.119 g, 0.38 mmol),2,4-difluorobenzaldehyde (0.054 g, 0.38 mmol) and NaBH(OAc)₃ (0.157 g,0.74 mmol) in CH₂Cl₂ (10 ml). Stir 3 h and add more aldehyde (0.016 g)and borohydride (0.045 g). Stir 18 h, dilute with CH₂Cl₂, and wash withsat. NaHCO₃, then brine. Dry (MgSO₄) and concentrate. Purify on PLC toobtain the title compound as a colorless oil, MS: m/e 440 (M+1).

EXAMPLE 19

Step 1:

Combine 2,4-difluorobromobezene (2.00 g, 10.4 mmol), 4-piperazinoneethylene ketal (2.27 g, 15.5 mmol), NaO-tBu (1.39 g, 14.5 mmol), ±-BINAP(0.387 g, 0.65 mmol), and Pd₂(dba)₃ (0.119 g, 0.21 mmol) in toluene (20ml). Heat at reflux 18 h, allow to cool, and oncentrate. Chromatographon silica to obtain a brown oil.

Step 2:

Combine the product of Step 1 (2.55 g, 10.0 mmol) and 5N HCl (40 ml) inTHF (25 ml). Stir 5 d and basify with NH₄OH. Concentrate and partitionbetween CH₂Cl₂ and water. Wash with brine, dry (MgSO₄) and concentrateto obtain a brown oil.

Step 3:

Cool the product of Step 2 (1.75 g, 8.3 mmol) in MeOH (15 ml) in ice andadd NaBH₄ (0.16 g, 4.1 mmol). Stir 1 h, pour on ice and extract withCH₂Cl₂. Wash with brine, dry (MgSO₄) and concentrate to obtain a yellowoil.

Step 4:

Combine the product of Step 3 (1.65 g, 7.7 mmol) and Et₃N in CH₂Cl₂ (30ml). Cool in ice and add methanesulfonyl chloride (1.07 g, 9.4 mmol).Stir 1 h and wash with sat. NaHCO₃. Dry (MgSO₄) and concentrate toobtain a yellow oil.

Step 5:

Dissolve the product of Step 4 (1.00 g, 3.4 mmol) in EtOH (10 ml). Add40% aqueous MeNH₂ (20 ml, 0.2 mol). Heat in a sealed tube at 100° C. for3 h, allow to cool, and concentrate. Partition between CH₂Cl₂ and water.Wash with brine, dry (MgSO₄) and concentrate. Purify on PLC to obtain ayellow oil.

Step 6:

Combine the product of Step 5 (0.035 g, 0.15 mmol) with the product ofExample 5, Step 2 (0.041 mg, 0.18 mmol) and K₂CO₃ (0.031 g, 0.23 mmol)in DMF (3 ml). Heat at 140° C. for 18 h. Concentrate and purify by PLCto obtain the title compound as a colorless gum, MS: m/e 426 (M+1).

Because of their adenosine A_(2a) receptor antagonist activity,compounds of the present invention are useful in the treatment ofdepression, cognitive function diseases and neurodegenerative diseasessuch as Parkinson's disease, senile dementia as in Alzheimer's disease,and psychoses of organic origin. In particular, the compounds of thepresent invention can improve motor-impairment due to neurodegenerativediseases such as Parkinson's disease.

The other agents known to be useful in the treatment of Parkinson'sdisease that can be administered in combination with the compounds offormula I include: L-DOPA; dopaminergic agonists such as quinpirole,ropinirole, pramipexole, pergolide and bromocriptine; MAO-B inhibitorssuch as deprenyl and selegiline; DOPA decarboxylase inhibitors such ascarbidopa and benserazide; and COMT inhibitors such as tolcapone andentacapone. One to three other agents can be used in combination withthe compounds of formula I, preferably one.

The pharmacological activity of the compounds of the invention wasdetermined by the following in vitro and in vivo assays to measureA_(2a) receptor activity.

Human Adenosine A_(2a) and A₁ Receptor Competition Binding AssayProtocol

Membrane Sources:

-   A_(2a): Human A_(2a) Adenosine Receptor membranes, Catalog #RB-HA2a,    Receptor Biology, Inc., Beltsville, Md. Dilute to 17 μg/100 μl in    membrane dilution buffer (see below).    Assay Buffers:-   Membrane dilution buffer: Dulbecco's Phosphate Buffered Saline    (Gibco/BRL)+10 mM MgCl₂.-   Compound Dilution Buffer: Dulbecco's Phosphate Buffered Saline    (Gibco/BRL)+10 mM MgCl₂ supplemented with 1.6 mg/ml methyl cellulose    and 16% DMSO. Prepared fresh daily.    Ligands:-   A_(2a): [3H]-SCH 58261, custom synthesis, AmershamPharmacia Biotech,    Piscataway, N.J. Stock is prepared at 1 nM in membrane dilution    buffer. Final assay concentration is 0.5 nM.-   A₁: [3H]-DPCPX, AmershamPharmacia Biotech, Piscataway, N.J. Stock is    prepared at 2 nM in membrane dilution buffer. Final assay    concentration is 1 nM.    Non-Specific Binding:-   A_(2a): To determine non-specific binding, add 100 nM CGS 15923    (RBI, Natick, Mass.). Working stock is prepared at 400 nM in    compound dilution buffer.-   A₁: To determine non-specific binding, add 100 μM NECA (RBI, Natick,    Mass.). Working stock is prepared at 400 μM in compound dilution    buffer.    Compound Dilution:-   Prepare 1 mM stock solutions of compounds in 100% DMSO. Dilute in    compound dilution buffer. Test at 10 concentrations ranging from 3    μM to 30 pM. Prepare working solutions at 4× final concentration in    compound dilution buffer.    Assay Procedure:

Perform assays in deep well 96 well plates. Total assay volume is 200μl. Add 50 μl compound dilution buffer (total ligand binding) or 50 μlCGS 15923 working solution (A_(2a) non-specific binding) or 50 μl NECAworking solution (A₁ non-specific binding) or 50 μl of drug workingsolution. Add 50 μl ligand stock ([3H]-SCH 58261 for A_(2a), [3H]-DPCPXfor A₁). Add 100 μl of diluted membranes containing the appropriatereceptor. Mix. Incubate at room temperature for 90 minutes. Harvestusing a Brandel cell harvester onto Packard GF/B filter plates. Add 45μl Microscint 20 (Packard), and count using the Packard TopCountMicroscintillation Counter. Determine IC₅₀ values by fitting thedisplacement curves using an iterative curve fitting program (Excel).Determine Ki values using the Cheng-Prusoff equation.

Haloperidol-Induced Catalepsy in the Rat

Male Sprague-Dawley rats (Charles River, Calco, Italy) weighing 175–200g are used. The cataleptic state is induced by the subcutaneousadministration of the dopamine receptor antagonist haloperidol (1 mg/kg,sc), 90 min before testing the animals on the vertical grid test. Forthis test, the rats are placed on the wire mesh cover of a 25×43plexiglass cage placed at an angle of about 70 degrees with the benchtable. The rat is placed on the grid with all four legs abducted andextended (“frog posture”). The use of such an unnatural posture isessential for the specificity of this test for catalepsy. The time spanfrom placement of the paws until the first complete removal of one paw(decent latency) is measured maximally for 120 sec.

The selective A_(2A) adenosine antagonists under evaluation areadministered orally at doses ranging between 0.3 and 3 mg/kg, 1 and 4 hbefore scoring the animals.

6-OHDA Lesion of the Middle Forebrain Bundle in Rats

Adult male Sprague-Dowley rats (Charles River, Calco, Como, Italy),weighing 275–300 g, are used in all experiments. The rats are housed ingroups of 4 per cage, with free access to food and water, undercontrolled temperature and 12 hour light/dark cycle. The day before thesurgery the rats are fasted over night with water ad libitum.

Unilateral 6-hydroxydopamine (6-OHDA) lesion of the middle forebrainbundle is performed according to the method described in Ungerstedt etal, Brian Research, 24 (1970), p. 485–493, and Ungerstedt, Eur. J.Pharmacol., 5 (1968), p. 107–110, with minor changes. Briefly, theanimals are anaesthetized with chloral hydrate (400 mg/kg, ip) andtreated with desipramine (10 mpk, ip) 30 min prior to 6-OHDA injectionin order to block the uptake of the toxin by the noradrenergicterminals. Then, the animals are placed in a stereotaxic frame. The skinover the skull is reflected and the stereotaxic coordinates (−2.2posterior from bregma (AP), +1.5 lateral from bregma (ML), 7.8 ventralfrom dura (DV) are taken, according to the atlas of Pellegrino et al(Pellegrino L. J., Pellegrino A. S. and Cushman A. J., A StereotaxicAtlas of the Rat Brain, 1979, New York: Plenum Press). A burr hole isthen placed in the skull over the lesion site and a needle, attached toa Hamilton syringe, is lowered into the left MFB. Then 8 μg 6-OHDA-HClis dissolved in 4 μl of saline with 0.05% ascorbic acid as antioxidant,and infused at the constant flow rate of 1 μl/1 min using an infusionpump. The needle is withdrawn after additional 5 min and the surgicalwound is closed and the animals left to recover for 2 weeks.

Two weeks after the lesion the rats are administered with L-DOPA (50mg/kg, ip) plus Benserazide (25 mg/kg, ip) and selected on the basis ofthe number of full contralateral turns quantified in the 2 h testingperiod by automated rotameters (priming test. Any rat not showing atleast 200 complete turns/2 h is not included in the study.

Selected rats receive the test drug 3 days after the priming test(maximal dopamine receptor supersensitivity). The new A_(2A) receptorantagonists are administered orally at dose levels ranging between 0.1and 3 mg/kg at different time points (i.e., 1, 6, 12 h) before theinjection of a subthreshold dose of L-DOPA (4 mpk, ip) plus benserazide(4 mpk, ip) and the evaluation of turning behavior.

Using the above test procedures, the following results were obtained forpreferred and/or representative compounds of the invention.

Results of the binding assay on compounds of the invention showed A_(2a)Ki vaules of about 0.3 to about 50 nM, with preferred compounds showingKi values between 0.3 and 10 nM.

Selectivity is determined by dividing Ki for A1 receptor by Ki for A2areceptor. Compounds of the invention have a selectivity ranging fromabout 1 to about 1600. Preferred are compounds are those wherein theselectivity is >100.

Preferred compounds showed about a 50–75% decrease in descent latencywhen tested orally at 1–3 mg/kg for anti-cataleptic activity in rats.

One to three compounds of formula I can be administered in the method ofthe invention, preferably one.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection.

Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The quantity of active compound of formula I in a unit dose ofpreparation may be varied or adjusted from about 0.1 mg to 1000 mg, morepreferably from about 1 mg to 300 mg, according to the particularapplication.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

The amount and frequency of administration of the compounds of theinvention and the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regimen for compounds of formula I is oral administration of from10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to fourdivided doses to provide relief from central nervous system diseasessuch as Parkinson's disease. The compounds are non-toxic whenadministered within this dosage range.

The doses and dosage regimen of the other agents used in the treatmentof Parkinson's disease will be determined by the attending clinician inview of the approved doses and dosage regimen in the package insert,taking into consideration the age, sex and condition of the patient andthe severity of the disease. It is expected that when the combination ofa compound of formula I and a another anti-Parkinson's disease agent isadministered, lower doses of the components will be effective comparedto the doses of the components administered as monotherapy. Whenadministered in combination, the compound(s) of formula I and the otheragent(s) for treating Parkinson's disease can be administeredsimultaneously or sequentially. This is particularly useful when thecomponents of the combination are preferably given on different dosingschedules, e.g., one component is administered daily and another everysix hours, or when the preferred pharmaceutical compositions aredifferent, e.g. one is preferably a tablet and one is a capsule. A kitcomprising the separate dosage forms is therefore advantageous.

The following are examples of pharmaceutical dosage forms which containa compound of the invention. Those skilled in the art will recognizethat dosage forms can be modified to contain both a compound of formulaI and a dopaminergic agent. The scope of the invention in itspharmaceutical composition aspect is not to be limited by the examplesprovided.

PHARMACEUTICAL DOSAGE FORM EXAMPLES Example A—Tablets

No. Ingredients mg/tablet mg/tablet 1. Active compound 100 500 2.Lactose USP 122 113 3. Corn Starch, Food Grade, as a 30 40 10% paste inPurified Water 4. Corn Starch, Food Grade 45 40 5. Magnesium Stearate 37 Total 300 700Method of Manufacture

Mix Item Nos. 1 and 2 in a suitable mixer for 10–15 minutes. Granulatethe mixture with Item No. 3. Mill the damp granules through a coarsescreen (e.g., ¼″, 0.63 cm) if necessary. Dry the damp granules. Screenthe dried granules if necessary and mix with Item No. 4 and mix for10–15 minutes. Add Item No. 5 and mix for 1–3 minutes. Compress themixture to appropriate size and weigh on a suitable tablet machine.

Example B—Capsules

No. Ingredient mg/capsule mg/capsule 1. Active compound 100 500 2.Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 4. MagnesiumStearate NF 7 7 Total 253 700Method of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10–15 minutes. AddItem No. 4 and mix for 1–3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A method of improving motor impairment due to Parkinson's Diseasecomprising administering to a mammal in need of such treatment aneffective amount of a compound of the structural formula

or a pharmaceutically acceptable salt thereof, wherein: A is N; R¹ andR^(1a) are independently selected from the group consisting of H,(C₁–C₆)-alkyl, halo, CN and —CF₃; Y is —O—, —S—, —SO—, —SO₂—,R⁵-heteroaryldiyl, R⁵-arylene or

p and q are independently 2–3; Q and Q¹ are independently selected fromthe group consisting of

provided that at least one of Q and Q¹ is

R is R⁵⁻aryl, R⁵⁻heteroaryl, R⁶-(C₂–C₆)alkenyl or R⁶—(C₂–C₆)alkynyl; R²is R⁵⁻aryl, R⁵⁻heteroaryl, R⁵⁻aryl(C₁–C₆)alkyl orR⁵⁻heteroaryl(C₁–C₆)alkyl; or R²—Y is

U, V, and W are independently selected from the group consisting of Nand CR¹, provided that at least one of U, V and W is CR¹; n is 1, 2 or3; and (a) X is —N(R⁹)—, Y is R⁵-arylene and R² is

 or n is 2 or 3; and (b) X is —C(R³)(R^(3a))—, —C(O)—, —O—, —S—, —SO—,—SO₂—, —N(R⁹)—, R⁴-arylene or R⁴-heteroaryldiyl; or Y is a bond and X is—C(O)—, —N(R⁹)—, R⁴-arylene or R⁴-heteroaryldiyl; or Y is N(R^(9a))—,—C(O)N(R^(9a))— or —O—(CH₂)₂—N(R^(9a))—, and X is —N(R⁹)—; or X is—N(R⁹)—, and Y and R² together are

 or n is 0; and (c) Y is a bond, X is —N(R⁹)—, and R² is

 or (d) X is —N(R⁹)— and Y and R² together are

 wherein Z is —C(O)-CH₂—, —C(O)—CH(C₁–C₆ alkyl)—, —CH₂—CH(C₁–C₆ alkyl)—,or —CH(C₁–C₆ alkyl)-CH₂—; R³ and R^(3a) are independently selected fromthe group consisting of H, —OH, C₁–C₆ alkyl, hydroxy(C₁–C₆)alkyl,(C₁–C₆)alkoxy(C₁–C₆)alkyl, amino(C₁–C₆)alkyl,(C₁–C₆)alkylamino(C₁–C₆)alkyl and di(C₁–C₆)alkylamino(C₁–C₆)alkyl; R⁴ is1–3 substituents selected from the group consisting of H, (C₁–C₆)alkyl,—OH, (C₁–C₆)alkoxy, (C₁–C₆)alkoxy(C₁–C₆)alkoxy, halo, —CF₃, and —CN; R⁵is 1–3 substituents independently selected from the group consisting ofH, (C₁–C₆)alkyl, —OH, (C₁–C₆)alkoxy, (C₁–C₆)alkoxy(C₁–C₆)alkyl, (C₁–C₆)alkoxy(C₁–C₆)-alkoxy, halo, —CF₃, —CN, —NH₂, (C₁–C₆)alkylamino,dl(C₁–C₆)alkylamino, amino (C₁–C₆)-alkyl, (C₁–C₆)alkylamino(C₁–C₆)alkyl,di(C₁–C₆)alkylamino(C₁–C₆)alkyl, (C₁–C₆) alkanoylamino,(C₁–C₆)alkanesulfonylamino, (C₁–C₆)alkylthio, (C₁–C₆)alkylthio (C₁–C₆)alkyl, R⁶—(C₂–C₆)alkenyl, R⁶—(C₂–C₆)alkynyl, hydroxy(C₁–C₆)alkyl,(C₁–C₆) alkoxy-C(O)-amino, or heterocycloalkyl(C₁–C₆)alkyl; R⁶ is 1 to 3substituents independently selected from the group consisting of H,(C₁–C₆)alkyl, —OH, (C₁–C₆)alkoxy and halo; R⁷ and R^(7a) areindependently selected from the group consisting of H, (C₁–C₆)alkyl,(C₁–C₆)alkoxy(C₁–C₆)alkyl, R⁸-aryl and R⁸-heteroaryl, or an R⁷ and anR^(7a) substituent on the same carbon can form ═O; R⁸ is 1 to 3substituents independently selected from H, (C₁–C₆)alkyl, —OH,(C₁–C₆)alkoxy, (C₁–C₆)alkoxy(C₁–C₆)alkoxy, halo, —CF₃, and CN; R⁹ andR^(9a) are independently selected from the group consisting of H,(C₁–C₆)alkyl, hydroxy(C₂–C₆)alkyl, (C₁–C₆)alkoxy(C₂–C₆)alkyl, amino(C₂–C₆)alkyl, (C₁–C₆)alkylamino(C₂–C₆)alkyl,dl(C₁–C₆)alkylamino(C₂–C₆)alkyl, halo-(C₃–C₆)alkenyl, CF₃-(C₁–C₆)alkyl,(C₃–C₆)alkenyl, -(C₃–C₆)cycloalkyl and (C₃–C₆)cycloalkyl-(C₁–C₆)alkyl;and R¹⁰ is H, —C(O)—O—(C₁–C₆)alkyl, R⁵-aryl, -C(O)-(C₁–C₆)alkyl,—C(O)—(R⁵-aryl) or R⁵-aryl-(C₁–C₆)alkyl.
 2. A method of claim 1 whereinthe compound is selected from the group consisting of compounds of theformula

wherein R²—Y—(CH₂)_(n)—N(R⁹)— is as defined in the table and Me meansmethyl: R²—Y—(CH₂)_(n)—N(R⁹)—


3. The method of claim 1 wherein X is —O—, —S—, —N(R⁹)— or R⁴-arylene.4. The method of claim 3 wherein R⁹ is methyl or ethyl.
 5. The method ofclaim 1 wherein Y is a bond or piperazinyl.
 6. The method of claim 1wherein R² is R⁵-aryl.
 7. The method of claim 1 wherein R is furyl. 8.The method of claim 1 wherein X is —O—, —S—, —N(R⁹)— or R⁴-arylene; R⁹is methyl or ethyl; Y is a bond or piperazinyl; R² is R⁵-aryl; and R isfuryl.
 9. The method of claim 8 wherein R⁵ is 1 or 2 substituentsselected from the group consisting of H, (C₁–C₆)alkoxy, (C₁–C₆)alkoxy(C₁–C₆)-alkoxy, halo and CF₃.